Abstract A number of genes, when mutated, have been shown to underlie the development of Parkinson?s disease (PD), including the Leucine Rich Repeat Kinase 2 gene (LRRK2). A number of studies have identified several mutations in the LRRK2 gene; each which result in an autosomal-dominant late-onset form of PD that have clinical and pathological phenotypes similar to idiopathic PD. Population studies have demonstrated that mutations in the LRRK2 gene account for approximately 13% of all diagnosed familial cases of PD and 5-10% of apparently sporadic PD cases. The two most common LRRK2 mutation, G2019S and R1441G, are located in the MAPKK and ROC GTPase domains, respectively. However, despite intensive research efforts, the precise mechanisms underlying LRRK2-induced parkinsonian pathology are still unclear. Additionally, low penetrance of LRRK2 mutations in humans, and the absence of an obvious neurological phenotype in LRRK2 animal models suggest that this form of PD may result from a complex interplay of genetic predispositions and persistent exogenous insults. preliminary studies in this application support a finding that R1441G and G2019S mutations in LRRK2 affect the functional crosstalk between the peripheral immune system and microglia of the innate immune system in the CNS. This alteration appears to mediate inflammation in the substantia nigra pars compacta (SNpc) and degeneration of SNpc DA neurons. based on our studies, and others in the literature, we hypothesize that neuroinflammation in the CNS of LRRK2 mice following an exogenous insult is not initiated by a direct effect on the brain?s intrinsic immune system (microglia) or through the actions of T-cells that have extravastated from the circulatory system into brain, but are triggered by dysregulated expression of peripheral circulating inflammatory molecules, including cytokines that can pass from the periphery into the brain. In this high risk/high reward application, we propose two specific aims to test this hypothesis. In SA1, we will use bone marrow transplantation to generate mice that express wt LRRK2 expression in T- and B-cells while all other cells (including neurons and microglia) express mutant LRRK2. In SA2, we will use these mice to determine if the replacement of mutant LRRK2 with wt LRRK2 in peripheral T- and B-cells diminishes the response to LPS-induced neuroinflammation and rescues the SNpc DA neuron loss seen in LPS-exposed mutant LRRK2 mice. If mice carrying wt T- and B-cells do not show pathological effects of LPS in the CNS, this will support the hypothesis that a major monogenic cause of PD is immune mediated rather than a direct effect of LRRK2 in the CNS; supporting a paradigm shift in our understanding of the etiology of PD as well as provide new targets for the treatment (and possibly prevention) of PD.